The Reaction of 2′-Deoxynucleosides with N-(2-Chloro1,1,2-trifluoroethyl)diethylamine: Mechanisms of O2,3′-Anhydro-2′-deoxynucleoside and By-product Formation

Article abstract of DOI:10.1039/a705686i

Reaction mechanisms consistent with the formation of isopropylidene-like trans-furanose-3′,5′-[2-(R)(S)-aminochlorofluoromethyl-1,3-dioxanyl] -2′-deoxynucleoside intermediates 6, O²,3′-anhydro-2′-deoxynucleosides 7 and other minor reaction products and the yield-limiting effect of 6 on the cyclization of 7 are proposed.

Full text of DOI:10.1039/a705686i

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24
J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
The Reaction of 2؅-Deoxynucleosides with N-(2-Chloro-
,1,2-trifluoroethyl)diethylamine: Mechanisms of
O ,3؅-Anhydro-2؅-deoxynucleoside and By-product
Formation
1
998, 24–25
1
J. Chem. Research (M),
998, 0301–0326
1
2
Raj K. Sehgal* and Joseph G. Turcotte
Department of Medicinal Chemistry, College of Pharmacy, University of Rhode Island,
Kingston, Rhode Island 02881, USA
Reaction mechanisms consistent with the formation of isopropylidene-like trans-furanose-3؅,5؅-[2-(R)(S)-aminochloro-
2
fluoromethyl-1,3-dioxanyl]-2؅-deoxynucleoside intermediates 6, O ,3؅-anhydro-2؅-deoxynucleosides 7 and other minor
reaction products and the yield-limiting effect of 6 on the cyclization of 7 are proposed.
In our ongoing efforts to develop anti-HIV liponucleotides
with distinct biophysical properties, the synthesis of the
immediate anhydro precursors (7a, 7b) of azidothymidine
and azidodeoxyuridine via reaction of 2؅-deoxynucleoside
series of compounds with N-(2-chloro-1,1,2-trifluoroethyl)-
We herein report our preliminary findings on the reaction
2
mechanism underlying the formation of O ,3؅-anhydronu-
cleosides and by-product analysis envisaged to optimize the
reaction conditions for this intriguing transformation.
The main features of the proposed mechanism as outlined
in Schemes I and II are an equilibrium between the trans-
5a,7,9
diethylamine (CTFDA) was investigated in detail.
H
O
N
O
R
Minor path a
N
O
HO
O
–
H
–
F +
N
F
O
N
O
R
ClFCH
F
Et
Et
+
N
Et
, DMF
ClFCH
N
O
Et
HO
5
HO
Major path b
H
O
N
O
R
1
a R = Me
b R = H
N
O
O
N
O
O
O
O
N
R
HO
ClFCH
Et
N
Et
7
(60%)
6
(15–20%)
Scheme I
O
N
O
R
O
N
O
R
O
N
O
R
O
N
O
R
N
O
N
N
O
N
O
O
O
HO
F
O
F
O
F
H
O
13
Me
N
O
Cl
7
10
12
Me
a R = Me
b R = H
O
N
O
R
O
N
O
O
N
O
R
N
N
N
O
O
O
R
O
O
O
–
F
F
OH
N
+
Et
Et
Et
ClFCH
N
ClFCH
N
ClFCH
Et
Et
Et
11
8
9
Scheme II
furanose intermediates 6 and 5, with the latter iminium
species undergoing intramolecular cyclization to form anhy-
dronucleosides 7.
*
†
To receive any correspondence.
This is a Short Paper as defined in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
To rationalize the formation of the minor novel product

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J. CHEM. RESEARCH (S), 1998 25
O
N
O
R
O
N
O
R
O
N
O
R
N
N
N
O
O
3
LiN , DMF
O
O
O
O
O
OH
N
+
N
Et
Et
ClFCH
ClFCH
Et
–
ClFCH
N3
N
Et
Et
9
Et
6
11
a R = Me
b R = H
H
N
H
N
H
O
N
O
R
O
O
O
O
N
O
LiN3, DMF
+
N
N
N
N
O
O
O
O
R
R
R
HO
HO
HO
N3
O
N3
N3
N3
7
14
15
17
H
O
N
O
N
O
R
TsO
N3
16
Scheme III
1
1
3a, analogous intermediates 8a, 9a and 12a are invoked. The
Techniques used: H NMR, MS, IR
extremely acidic hydrogen atom of the chlorofluoromethyl
group of 12a is readily removed via base, with the resulting
intermediate fluorocarbene inserting into the CsH bond of
the solvent (DMF); elimination of hydrogen chloride to the
enolate gives rise to the isolated ester 13a (preferred keto
form).
Azide displacements on the stable bicyclic intermediates 6
with lithium azide in DMF afforded the corresponding disub-
stituted derivatives 17 (Scheme III) via the likely inter-
mediates 11 and 9. The stereochemical course of the result-
ing diazido nucleosides having the 3؅-a-stereochemistry was
ascertained and confirmed by an independent synthetic
route.
References: 18
Schemes: 4
Received, 5th August 1997; Accepted, 30th September 1997
Paper E/7/05686I
References cited in this synopsis
5 (a) R. P. Glinski, M. S. Khan and R. L. Kalamas, J. Org. Chem.,
1
973, 38, 4299.
7
9
G. Kowollik, K. Gaertner and P. Langen, Tetrahedron Lett., 1969,
863.
3
The products of reaction of 2؅-deoxycytidine with CTFDA
proved too unstable to isolate chromatographically (silica
gel).
R. L. Rideout, D. W. Barry, S. F. Lehrman, M. H. St. Clair, P. A.
Furman, L. M. Beecham II, H. S. LeBlanc and G. A. Freeman,
Eur. Pat. Appl., 86301896.6, 1986.